Physical activity and exercise confer beneficial effects on health giving rise to the concept that exercise is medicine. A key determinant of exercise performance is skeletal muscle as it comprises roughly half of the total body mass and is responsible for one-third of the resting metabolic rate in mammals. During states of heightened metabolic demand (e.g. low to moderate intensity exercise), lipids serve as the preferred physiologic substrate. Coordination of efficient lipid utilization occurs at multiple levels includng lipid uptake, delivery to the mitochondria, and oxidation. The expression and activity of these enzymatic steps are under robust transcriptional control; a transcriptional circuitry often ascribe to the nuclear receptor family of transcription factors, in particular PPAR?. However, the precise molecular basis by which these transcriptional responses are coupled to physiologic stimuli or dysregulated in disease remains poorly understood. As transcriptional control and molecular cooperativity are emerging themes in muscle performance, studies in this application investigate a skeletal muscle intrinsic role for a transcription factor termed Kruppel-like factor-15 (KLF15) through a novel molecular module involving PPAR?. Preliminary results central to this application identify skeletal muscle KLF15 as an essential regulator of muscle function and lipid metabolism. Specifically, mice bearing skeletal muscle specific overexpression or deletion of KLF15 demonstrate enhanced and reduced ability for endurance exercise capacity, respectively. Gene expression analysis reveals that KLF15 regulates the expression of genes involved in fat utilization, many of which are canonical targets of PPAR?. Critically, KLF15 binds to, cooperates with, and is requisite for the ability of PPAR? to induce a subset of target genes critical for skeletal muscle lipid utilization. On the basis of these observations, this applicatio seeks to test the hypothesis that a KLF15-PPAR? molecular module coordinates skeletal muscle lipid flux and exercise capacity. The goals of this application are: (1) To determine the importance of skeletal muscle KLF15 in exercise performance and lipid utilization; and (2) To elucidate the molecular basis of the KLF15-PPAR? cooperative module in skeletal muscle lipid metabolism. These results will provide molecular, cellular, and whole-organ insights regarding the role of KLF15 as a modulator of skeletal muscle lipid metabolism through a mechanism that involves, at least in part, cooperativity with PPAR?. The results of these studies may provide the foundation for novel therapies that potentiate the beneficial effects of exercise and combat obesity and diabetes.